A new study in Science Translational Medicine reports that the antimicrobial protein calprotectin is induced in neonatal intestinal epithelial cells in response to commensal bacteria. In mouse models, impaired calprotectin expression or poor microbiota colonization increased susceptibility to sepsis and death, while calprotectin supplementation rescued microbiota-depleted pups. The work links early-life microbial signals to epithelial S100A8/A9 program activation. It also identifies the metabolite indole-3-lactic acid (ILA) produced by commensal Lactobacillus as a driver of neonatal epithelial calprotectin production, including mechanistic validation in organoid systems. For neonatal care and product development, the findings strengthen the scientific rationale for targeting host–microbe signaling pathways to improve early immune robustness, rather than focusing only on later-life immune modulation.